Glutathione S‐Transferase A1 Genetic Variants Reduce Busulfan Clearance in Children Undergoing Hematopoietic Cell Transplantation

The effect of glutathione S‐transferase variants on pediatric busulfan metabolism was investigated by noncompartmental and population pharmacokinetic modeling. Twenty‐nine children who underwent related or unrelated bone marrow or umbilical cord blood hematopoietic cell transplant were retrospectively studied. GSTA1, GSTP1, and GSTM1 variants were explored for their effects on busulfan exposures. Noncompartmental pharmacokinetic analyses showed that carriers of GSTA1*B had a 2.6‐fold higher busulfan area under the curve and concentration at steady state compared with noncarriers (i>P< ≤ .01). Population pharmacokinetic modeling demonstrated that carriers of GSTA1*B reduced busulfan clearance by 30%. Monte Carlo simulations were then performed to assess busulfan dosing regimens based on GSTA1 genotypes. Simulations determined that dosing based on GSTA1 genotype, weight, and age resulted in fewer children exceeding the upper therapeutic limit compared with dosing using age and weight only. Larger, prospective studies are needed to confirm these findings.

[1]  G. Vassal,et al.  Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring , 2007, Cancer Chemotherapy and Pharmacology.

[2]  L. Dupuis,et al.  Pharmacokinetic disposition and clinical outcomes in infants and children receiving intravenous busulfan for allogeneic hematopoietic stem cell transplantation. , 2007, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  J. Gobburu,et al.  Population Pharmacokinetic–Based Dosing of Intravenous Busulfan in Pediatric Patients , 2007, Journal of clinical pharmacology.

[4]  S. Ogawa,et al.  Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[5]  R. Ueda,et al.  Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation , 2006, Bone Marrow Transplantation.

[6]  J. Robert,et al.  Predicting drug response and toxicity based on gene polymorphisms. , 2005, Critical reviews in oncology/hematology.

[7]  B. George,et al.  Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation. , 2004, Blood.

[8]  L. Nguyen,et al.  I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients , 2004, Bone Marrow Transplantation.

[9]  Y. Théorêt,et al.  Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results , 2003, Bone Marrow Transplantation.

[10]  J. Niland,et al.  Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[11]  P. Thall,et al.  Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[12]  F. Appelbaum,et al.  Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation , 2002, Bone Marrow Transplantation.

[13]  M. Eichelbaum,et al.  Genetic polymorphisms of glutathione S‐transferase A1, the major glutathione S‐transferase in human liver: Consequences for enzyme expression and busulfan conjugation , 2002, Clinical pharmacology and therapeutics.

[14]  S. Cremers,et al.  Pharmacokinetics of intravenous busulfan in children prior to stem cell transplantation. , 2002, British journal of clinical pharmacology.

[15]  P. Vineis,et al.  Metabolic gene polymorphism frequencies in control populations. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[16]  B. Green,et al.  Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression. , 2001, Pharmacogenetics.

[17]  M. Scholl,et al.  Busulfan levels are influenced by prior treatment and are associated with hepatic veno-occlusive disease and early mortality but not with delayed complications following marrow transplantation , 2001, Bone Marrow Transplantation.

[18]  M. Chandy,et al.  Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[19]  B. Bostrom,et al.  An evaluation of engraftment, toxicity and busulfan concentration in children receiving bone marrow transplantation for leukemia or genetic disease , 2000, Bone Marrow Transplantation.

[20]  R. Baldassano,et al.  Up-regulation of glutathione S-transferase activity in enterocytes of young children. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[21]  L. Law,et al.  Routine analysis of plasma busulfan by gas chromatography-mass fragmentography. , 1998, Clinical chemistry.

[22]  J. Slattery,et al.  Therapeutic monitoring of busulfan in hematopoietic stem cell transplantation. , 1998, Therapeutic drug monitoring.

[23]  S. Amin,et al.  Specificities of human glutathione S-transferase isozymes toward anti-diol epoxides of methylchrysenes. , 1998, Carcinogenesis.

[24]  J. Chien,et al.  Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan. , 1997, Cancer research.

[25]  H. Deeg,et al.  Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. , 1997, Blood.

[26]  J. Gibbs,et al.  Busulfan conjugation by glutathione S-transferases alpha, mu, and pi. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[27]  J. Gibbs,et al.  Busulfan-glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases. , 1996, Cancer research.

[28]  J. Wingard,et al.  Association of busulfan area under the curve with veno-occlusive disease following BMT. , 1996, Bone marrow transplantation.

[29]  F. Appelbaum,et al.  Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. , 1995, Bone marrow transplantation.

[30]  G. Vassal,et al.  Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation , 1995, Cancer Chemotherapy and Pharmacology.

[31]  L. Grochow.  Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens. , 1993, Seminars in oncology.

[32]  L. Grochow,et al.  VENOOCCLUSIVE DISEASE OF THE LIVER FOLLOWING BONE MARROW TRANSPLANTATION , 1987, Transplantation.

[33]  R. Egeler,et al.  Intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics in association with early clinical outcome and toxicity , 2005, Bone Marrow Transplantation.

[34]  J. Gibbs,et al.  Plasma concentration monitoring of busulfan: does it improve clinical outcome? , 2000, Clinical pharmacokinetics.

[35]  Albert,et al.  Busulfan bioavailability. , 1994, Blood.

[36]  P. Shaw,et al.  Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia. , 1994, Blood.